This invention relates to pharmaceutical formulations of lipophilic therapeutic agents in which such agents are solubilized in largely aqueous vehicles, and uses for such formulations. The formulations are stable in aqueous-based vehicles, and have therapeutically and commercially useful concentrations of active ingredient.
Many pharmacologically active substances are lipophilic, i.e., only sparingly or negligibly water-soluble. Lipophilic therapeutic agents span the entire range of biologically and/or pharmacologically active substances. For example, they include certain analgesics and anti-inflammatory agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-neoplastic agents and immunosuppressants, β-blockers, corticosteroids, opioid analgesics, lipid regulating agents, anxiolytics, sedatives, hypnotics and neuroleptics.
The poor water-solubility of these lipophilic agents often results in major difficulties in formulation, particularly when easily sterilizable and administrable homogeneous aqueous solutions are needed. Efficacious aqueous-based formulations are particularly problematic for systemic administration, in particular parenteral administration (i.e., injectable solutions) and for certain liquid preparations for, e.g., topical gynecologic, dermatologic ophthalmic, etc. use, and for use on the oral mucous membranes.
A number of approaches for obtaining aqueous compositions of sparingly water-soluble drugs are known. Such approaches seek to increase the solubility, and accordingly, increase the ease of formulation and the bioavailability of the sparingly soluble or lipophilic active agents. One such approach involves chemical modification of the lipophilic drug by introduction of a ionic or ionizable group or a group that lowers the melting point. The former generally depends upon the lipophilic drug having a hydroxyl or carboxy group which can be used to form various kinds of esters. The latter is based on the concept that, to be solubilized, the molecules have to leave the crystal lattice. Any modification of the molecule that lowers the melting point, and thus reduces the energy of the crystal lattice, tends to increase the solubility thereof in any solvent.
Another method involves physico-chemical solubilization techniques such as micellar solubilization by means of surface-active agents, i.e., the use of surfactant micelles to solubilize and transport the therapeutic agent. Micelles are agglomerates of colloidal dimensions formed by amphiphilic compounds under certain conditions. Micelles, and pharmaceutical compositions containing micelles, have been extensively studied and are described in detail in the literature. In aqueous solution, micelles can incorporate lipophilic therapeutic agents in the hydrocarbon core of the micelle, or can entangle the agents at various positions within the micelle walls. Although micellar formulations can solubilize a variety of lipophilic therapeutic agents, the loading capacity of conventional micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many lipophilic therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
The formation of complexes, solid solutions and solid dispersions by means of the use of suitable polymers is another approach for increasing the water-solubility of pharmaceutically active substances. In such a case, the active ingredient is incorporated in a suitable hydrophilic carrier, which increases the solubility and the bioavailability thereof without any formal covalent bonds originating between the drug and the polymer matrix. The difference between a solid solution and a solid dispersion is typically in the form of the active ingredient. In a solid solution, the active is present in the amorphous molecular form, while in a dispersion the active is present in a crystalline form, as fine as possible.
Even more widespread and studied is the use of the interaction between a polymer and a drug to give rise to a true complex, wherein chemical bonds of a noncovalent nature are involved. Complexing polymers employed in the pharmaceutical field include, e.g., polyethylene glycols, polypropylene glycols, cyclodextrins, carboxymethylcellulose, polyvinylpyrrolidone (PVP)
Co-precipitation is yet another widespread method for the preparation of complexes with increased solubility. In this method, the substance and the polymer are dissolved in an organic solvent in which they are both soluble, and the solution is then evaporated at atmospheric pressure, under vacuum, by spray-drying or by lyophilization, to yield a dry product actually made of the complex of the treated drug. Such complexes can also be obtained by applying other methods, such as grinding and mixing the ingredients in a mill, or by extrusion of a paste containing the two products together with a minor amount of water, etc. In comparison with the starting drug, the complex typically shows an appreciably enhanced water-solubility.
In devising a working method for solubilizing drugs by complexation, it is necessary to take into account the molecular weight of the polymer, since the solubility of the active ingredient directly depends thereon. In general, low molecular weights are more suitable than medium to high molecular weights.
Still another method involves use of various co-solvent systems, i.e., compositions using a solvent mixture containing water and one or more organic solvents. One approach to solubilizing lipophilic drug agents in aqueous systems is to employ some combination of alcohols and glycols (PDA J. Pharm. Sci. Technol. 50(5) 1996; U.S. Pat. Nos. 6,136,799; 6,361,758 and 5,858,999) Organic contents as high as 50% or more are often required to ensure solubility during manufacturing, storage and administration. Although organic levels while high will still be below the LD50 for a low volume parenteral dosage, the amounts are still typically undesirable. High levels of organic solvent can cause pain on injection and tissue necrosis.
Other methods involve the formation of complexes by the addition of chelating agents such as citric acid, tartaric acid, amino acids, thioglycolic acid and edetate disodium. Others use buffering agents such as acetate, citrate, glutamate and phosphate salts. However, buffers and chelating agents have been implicated in imparting aluminum levels in products to in excess of 3.5 parts per million leading to adverse side effects. (International Patent Application Publication WO 96/36340) Moreover, certain chelating agents such as EDTA have be implicated in adverse effects such nephrotoxicity and renal tubular necrosis. (U.S. Pat. No. 6,361,758)
Each of these foregoing methods has its inherent limitations. For many of the pharmaceutical substances, the solubility levels that can be achieved with one or another of the methods discussed above are still insufficient to make their use in aqueous-based commercial products viable.
An exemplary and important class of lipophilic drug agents are the vitamin D compounds. Properly metabolized vitamin D compounds are necessary for the maintenance of healthy bones and have been found to display more other biological activities. The lipophilicity of the natural forms of vitamin D and of the many known synthetic analogs of vitamin D makes it difficult to manufacture an efficacious formulation, particularly, a parenteral formulation which is preferred for, e.g., renal dialysis patients.
Additionally, vitamin D compounds, among other lipophilic compounds, are known to be oxygen sensitive, being oxidized when exposed to air, and thus, losing integrity. One approach to circumventing this problem is to add an antioxidant directly to a formulation of the drug. However, certain antioxidants, such as ascorbic acid and sodium ascorbate, which are highly water soluble, will discolor in the course of performing their intended function. Buffers and/or chelating agents have also been added to decrease oxygen sensitivity thus maintaining active drug potency (U.S. Pat. Nos. 4,308,264; 4,948,788 and 5,182,274.) However, as noted above, buffers and chelating agents are known to introduce undesirable levels of aluminum into the product.
Thus, there is a need for pharmaceutical formulations of lipophilic therapeutic agents that overcome the limitations of the many known approaches.